This invention relates to a pharmaceutical combination of estrogen agonists/antagonists and agents that stimulate bone formation and increase bone mass, kits containing such combinations and the use of such combinations to treat conditions which present with low bone mass in mammals, including humans.
Osteoporosis is a systemic skeletal disease, characterized by low bone mass and deterioration of bone tissue, with a consequent increase in bone fragility and susceptibility to fracture. In the U.S., the condition affects more than 25 million people and causes more than 1.3 million fractures each year, including 500,000 spine, 250,000 hip and 240,000 wrist fractures annually. Hip fractures are the most serious, with 5-20% of patients dying within one year, and over 50% of survivors being incapacitated.
The elderly are at greatest risk of osteoporosis, and the problem is therefore predicted to increase significantly with the aging of the population. Worldwide fracture incidence is forecast to increase three-fold over the next 60 years, and one study estimates that there will be 4.5 million hip fractures worldwide in 2050.
Women are at greater risk of osteoporosis than men. Women experience a sharp acceleration of bone loss immediately following menopause. Other factors that increase bone loss leading to osteoporosis include smoking, alcohol abuse, a sedentary lifestyle and low calcium intake.
Estrogen is the agent of choice in preventing osteoporosis or post menopausal bone loss in women. In addition, Black, et al. in EP 0605193A1 report that estrogen, particularly when taken orally, lowers plasma levels of LDL and raises those of the beneficial high density lipoproteins (HDL's). Long-term estrogen therapy, however, has been implicated in a variety of disorders, including an increase in the risk of uterine cancer, endometrial cancer and possibly breast cancer, causing many women to either avoid this treatment or take the medication for only a short period of time. Although the risk of endometrial cancer is thought to be reduced by a concurrent use of a progesterone, there is still concern about possible increased risk of breast cancer with the use of estrogen. Recently suggested therapeutic regimens, which seek to lessen the cancer risk, such as administering combinations of progesterone and estrogen, cause the patient to experience unacceptable bleeding. Furthermore, combining progesterone with estrogen seems to blunt the serum cholesterol lowering effects of estrogen. The significant undesirable side effects associated with estrogen therapy support the need to develop alternative therapies for osteoporosis that have the desirable beneficial effect on serum LDFL but do not cause undesirable side effects.
Recently, a number of estrogen agonists/antagonists have been proposed for treatment of osteoporosis. It has been reported (Osteoporosis conference Scrip No. 1812/13 Apr. 16/20, 1993, p. 29) that raloxifene, 6-hydroxy-2-(4-hydroxyphenyl)-3-[4-(2-piperidinoethoxy) benzoyl]benzo[b] thiophene, mimics the favorable action of estrogen on bone and lipids but, unlike estrogen, has minimal uterine stimulatory effect. [Black, L. J. et al., Raloxifene (LY139481 Hcl) Prevents Bone Loss and Reduces Serum Cholesterol Without Causing Uterine Hypertrophy in Ovariectomized Rats, J. Clin. Invest., 1994, 93:63-69].
Also, tamoxifen, 1-(4-.beta.-dimethylaminoethoxyphenyl)-1,2-diphenyl-but-1-ene, is an antiestrogen that is proposed as an osteoporosis agent which has a pallative effect on breast cancer, but is reported to have some estrogenic activity in the uterus. Gil-Sharma, et al., J. Reproduction and Fertility (1993) 99, 395, disclose that tamoxifen at 200 and 400 mg/kg/day reduces the weights of the testes and secondary sex organs in male rats.
In addition U.S. Pat. No. 5,254,594 (the disclosure of which is hereby incorporated by reference) discloses the use of droloxifene for the treatment of bone diseases including osteoporosis.
Agents such as droloxifene prevent bone loss and thereby reduce the risk of fracture without estrogen's side effects. However, estrogen and estrogen agonists alone are only expected to reduce the fracture risk by about 50% leaving approximately 50% of ostepenic women still at risk for an osteoporotic fracture.
Non-estrogen agonists/antagonists such as bisphosphonates are also proposed for the treatment of osteoporosis. For example, Fosamax.RTM. is a bisphosphonate that is currently marketed for the treatment of osteoporosis. Other bisphosphonates currently undergoing regulatory review include risedronate, tiludronate, and ibandronate.
Frost et al. in "Treatment of Osteoporosis by Manipulation of Coherent Bone Cell Populations", Clinical Orthopedics and Related Research, 143, 227 (1979) discloses a theoretical model that suggests it should be possible to synchronize the activity and metabolism of bone cells by administering a bone cell activating agent first, followed by a bone resorption inhibiting agent and then normal bone formation is allowed to occur.
Tang et al., Restoring and Maintaining Bone in Osteogenic Female Rat Skeleton: I. Changes in Bone Mass and Structure, J. Bone Mineral Research 7 (9), p1093-1104, 1992 discloses data for the lose, restore and maintain (LRM) concept, a practical approach for reversing existing osteoporosis. The LRM concept uses anabolic agents to restore bone mass and architecture (+phase) and then switches to an agent with the established ability to maintain bone mass, to keep the new bone (+/- phase). The rat study utilized PGE.sub.2 and risedronate, a bisphosphonate, to show that most of the new cancellous and cortical bone induced by PGE.sub.2 can be maintained for at least 60 days after discontinuing PGE.sub.2 by administering risedronate.
Combinations of bisphosphonates and prostaglandins for the treatment of osteoporosis are disclosed. E.P. App. No. 0 381 296 teaches the use of a kit wherein a bone activating period or treatment regime is followed by a bone resorption inhibiting regime. Examples of bone activating compounds cited in this reference include parathyroid hormone (PTH), inorganic phosphate, growth hormone, fluoride, thyroid hormone (e.g., thyroxin), certain vitamin D metabolites and prostaglandins (PGE.sub.2 in a dose regime of 10 mg/kg per day). Polyphosphonates are disclosed as the bone resorption inhibiting agents.
PCT/US93/08529 discloses the simultaneous delivery of a bone activating agent such as a prostaglandin that is chemically coupled to a bone resorption inhibiting compound which selectively delivers the bone activity agent to the target area. Upon gradual hyrolysis of the novel compound, the hydrolyzed products are able to provide bone resorption inhibiting activity (via the bisphosphonates) and bone growth or stimulating activity (via PGE.sub.2).
The effects of a combination of prostaglandin E2 and risedronate (a bisphosphonate) was studied in Lin et al., Effects of Prostaglandin E2 and Risedronate Administration on Cancellous Bone in Older Female Rats, Bone 15 (5), p489-496, 1994.
Qiu et al., Experimental Study on Antiatherosclerotic Treatment by PGE.sub.2 Combined With Vitamin E and Estradiol, Chinese Medical Journal, 108 (1) p33-36, 1995 disclose that a single dose of PGE.sub.2 combined with vitamin E and with estradiol had more coordinative inhibition on aortic and coronary atherosclerotic lesions, as well as on platelet aggregation, smooth muscle cell proliferation and lipid peroxidation than that of a single dose of PGE.sub.2.
The abstract for "Nonhormonal Alternatives for the Management of Early Menopause in Younger Women with Breast Cancer", Monogr. Natl. Cancer Inst. (16), 161-167, 1994, states "The use of several nonestrogen approaches for the prevention and treatment of osteoporosis has been promising. Traditional recommendations to maintain skeletal integrity, such as weight-bearing exercise; a diet rich in calcium and limited in caffeine, alcohol, and protein; avoidance of smoking; and measures to minimize trauma have been expanded to include the use or investigation of drugs (either alone or in combination). These drugs include progestins, vitamin D metabolites, injectable and intranasal synthetic salmon calcitonin, bisphosphonates, sodium fluoride, parathyroid hormone, growth factors, tamoxifen, etc."
Thus, although there exist a variety of osteoporosis therapies there is a continuing need and a continuing search in this field of art for alternative therapies due to only limited success of current therapies in reducing osteoporotic fractures.